The complement system is a rapid, protective mechanism that forms a significant part of the body’s innate immune defenses, designed to quickly identify and eliminate threats like bacteria and viruses. At the beginning of one of the main pathways sits C1q, a complex protein that serves as the primary recognition component. C1q is the molecular switch that initiates a cascade of events leading to inflammation, pathogen clearance, and tissue maintenance.
Structure and Identification
C1q is a large, multi-component protein assembled from eighteen polypeptide chains, giving it a unique and recognizable shape. The entire molecule is often described as resembling a small bouquet of six tulips. It features six collagen-like stalks that converge at one end and six globular head domains that fan out at the other, which are responsible for its recognition function.
C1q is the foundational component of the larger C1 complex, a giant proteolytic enzyme designed to initiate the cascade. The complete C1 complex consists of one C1q molecule bound to two molecules of C1r and two molecules of C1s, which are inactive serine proteases in the resting state. C1q acts as a pattern recognition molecule, sensing a wide variety of foreign or altered structures. These targets include invading pathogens, aggregated proteins, or the Fc regions of antibody isotypes like IgG and IgM when they are part of an immune complex.
Initiating the Classical Complement Cascade
The best-known function of C1q is triggering the classical pathway, linking the innate and adaptive immune responses. Initiation typically begins when C1q’s globular heads bind to the fragment crystallizable (Fc) region of specific antibodies (IgM or IgG subclasses) complexed with an antigen. Binding to an immune complex causes a conformational change, signaling the C1r and C1s components.
This shift activates the two associated C1r molecules, converting them into active serine proteases. The activated C1r enzymes then cleave and activate the C1s molecules within the C1 complex. Once activated, C1s cleaves the next two proteins in the pathway: C4 and C2.
C1s splits C4 into C4a and C4b, and C2 into C2a and C2b. The larger fragments, C4b and C2a, remain attached to the target surface and associate to form the C3 convertase enzyme. This convertase cleaves thousands of C3 molecules, marking the target for phagocytosis and driving the cascade forward. C1q can also directly recognize non-antibody activators, such as microbial surface proteins or aggregated proteins, bypassing the need for an immune complex to begin the cascade.
Roles Beyond Immune Defense
While its immune function is well-studied, C1q also performs significant duties outside of pathogen defense, especially in maintaining healthy tissues. One function is the prompt and silent clearance of cellular debris, particularly apoptotic cells. When cells undergo programmed cell death, C1q binds directly to their surface, acting as a “find me” signal for phagocytic cells like macrophages. This binding enhances the ingestion and removal of the dying cell, preventing the release of inflammatory contents.
C1q also plays an important role within the central nervous system (CNS) in synaptic pruning. Synaptic pruning is a normal developmental process where unnecessary neuronal connections are selectively eliminated to refine neural circuits. C1q tags these unwanted synapses, marking them for removal by specialized immune cells in the brain called microglia.
C1q and Associated Autoimmune Conditions
The functions of C1q are linked to preventing autoimmunity, evident in the consequences of its deficiency. An inherited C1q deficiency is a rare genetic condition, but it is the most predictive genetic factor for developing Systemic Lupus Erythematosus (SLE). Individuals with a complete C1q deficiency have an extremely high prevalence of developing SLE-like symptoms, often presenting with severe disease characteristics such as kidney and skin involvement.
The strong connection between C1q deficiency and SLE stems from a failure in the body’s cleanup mechanisms. Without functional C1q, the body struggles to efficiently clear immune complexes and the remnants of apoptotic cells. This accumulation of uncleared material leads to chronic inflammation and provides a continuous source of self-antigens, which drives the autoimmune response. C1q deficiency often leads to an early onset of the autoimmune disease compared to sporadic SLE.